Toxoplasma gondii is the causative agent of toxoplasmosis. For most of the estimated 60 million US citizens that have been exposed to the Toxoplasma parasite, most will have very few symptoms because a healthy person's immune system usually keeps the parasite from causing illness. However, pregnant women and individuals who have compromised immune systems are vulnerable to the full spectrum of serious health problems caused by the disease including blindness, encephalitis, mental retardation, and death. Treatment of toxoplasmosis with available therapeutics is not ideal and does not eradicate the parasite from the patient and therefore re-infections may occur. Work Accomplished: We have discovered and seek to improve an entirely new type of drug for prevention and treatment of toxoplasmosis. With IC50 values in the low nanomolar and picomolar range our most active compounds, so-called, ELQs, are far more potent (in vitro) than any drug in clinical use today for treating toxoplasmosis. If these drugs prove to be safe and effective enough to go into actual use, the potential benefit is nothing less than saving lives and sparing many individuals from long-term neurological damage, as well as damage to other organs such as the eyes, liver and spleen, heart and lung. Work Proposed: Specific objectives to be pursued as part of the project plan include: (1) to optimize the chemical structure of the ELQ pharmacophore by continued synthesis and design of analogs, (2) to screen new derivatives for selective potency against T. gondii in vitro and in vivo and in rational combination with standard therapeutics, (3) to monitor the metabolic stability of lead candidate ELQs in vitro in microsomal preparations and to determine pharmacokinetics and pharmacodynamic parameters in vivo in mice, and (4) to investigate the mechanism underlying the selective and potent antitoxoplasmial effects of ELQs. Taken together, we're excited by the possibilities and the potential for new drug development for treatment of toxoplasmosis in humans. Relevance to NIAID's mission: A primary mission of the NIAID is to conduct and support research that helps to provide protection against emerging and chronic infectious diseases that represent a threat to public health. Bioterrorism represents a new threat to public health and to meet the challenges posed by biodefense, NIAID supports research on countermeasures to infectious agents (including Toxoplasma gondii) that may be weaponized for bioterrorism. The development of therapies to prevent or treat infectious diseases, including diseases that are caused by potential agents of bioterror, is fundamental to the ever-expanding mission served by NIAID. Thus, for a multiplicity of reasons including public health, protection of the unborn child from birth defects, as well as biodefense, the proposed project is entirely relevant to NIAID's mission. PUBLIC HEALTH RELEVANCE: We have discovered and seek to improve an entirely new type of drug for prevention and treatment of toxoplasmosis. If these drugs prove to be safe and effective enough to go into actual use, the potential benefit is nothing less than saving lives and sparing many individuals from long-term neurological damage, as well as damage to other organs such as the eyes, liver and spleen, heart and lung.